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Determination and Implications of Electroosmotic Transport In DETERMINATION AND IMPLICATIONS OF ELECTROOSMOTIC TRANSPORT IN THE BRAIN by Yifat Guy BS, University of Pittsburgh, 2004 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2011 UNIVERSITY OF PITTSBURGH Graduate Arts and Sciences This dissertation was presented by Yifat Guy It was defended on December 15, 2010 and approved by Dr. Shigeru Amemiya, Professor, Department of Chemistry Dr. Adrian Michael, Professor, Department of Chemistry Dr. Mats Sandberg, Professor, Department of Anatomy and Cell Biology, Gothenberg University Dissertation Advisor: Dr. Stephen G. Weber, Professor, Department of Chemistry ii Copyright © by Yifat Guy 2011 Reproduced with permission from: Guy Y, Sandberg M, Weber SG. Biophysical Journal. 2008;94(11):4561-4569. Guy Y, Muha RJ, Sandberg M, Weber SG. Analytical Chemistry. 2009;81(8):3001-3007. iii DETERMINATION AND IMPLICATIONS OF ELECTROOSMOTIC TRANSPORT IN THE BRAIN Yifat Guy, PhD University of Pittsburgh, 2011 Electroosmotic flow is a bulk fluid flow that influences solute transport through capillary conduits and porous material under the influence of an electric field. The magnitude of electroosmotic flow is proportional to the ζ-potential of the capillary or porous material. A porous material such as living tissue would need to have an appreciable ζ-potential to create electroosmotic flow in the interstitial space. Transporting solutes in and out of tissue by virtue of electroosmotic flow in principle has advantages such as avoiding pressure effects and sample dilution that accompany micropush-pull and microdialysis approaches. In order to assess the viability of this approach, it is necessary to know the ζ-potential in the tissue of interest. To address this, a method and apparatus was developed to measure the ζ-potential and tortuosity in tissue slices. The method was applied to organotypic hippocampal slice cultures. The apparatus was improved on in order to provide feedback control to maintain a constant electric field through the tissue culture. The ζ-potential of the organotypic tissue culture is -22 ± 0.8 mV and the tortuosity is 2.24 ± 0.10. With a ζ-potential of -22 mV, low electric fields applied to the brain will create electroosmotic flow. Electroosmotic flow can be directed to transport extracellular fluid from brain tissue into a conduit such as a sampling capillary. Furthermore, electroosmotic flow can be used in the opposite way to eject fluid and solutes from a capillary or pipette into brain tissue. The iv electroosmotic effect may be important in the widely used solute delivery method of iontophoresis. In iontophoresis, solutes are ejected into tissue via an applied current. Once in the tissue, solute transport is affected by the electroosmotic flow in the tissue and thus depends on the tissue ζ-potential. The dependence of solute transport on ζ-potential is illustrated using a set of poly(acrylamide-co-acrylic acid) hydrogels. A method of measuring the thickness of organotypic tissue cultures has also been developed. Characterization of ζ-potential and tortuosity provides the fundamentals for understanding electroosmotic flow through the extracellular space of brain tissue. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIV 1.0 INTRODUCTION ........................................................................................................ 1 1.1 ELECTROKINETIC TRANSPORT ................................................................. 2 1.2 PHYSICOCHEMICAL BRAIN PROPERTIES .............................................. 4 1.3 THE MODEL SYSTEM: ORGANOTYPIC HIPPOCAMPAL SLICE CULTURE ............................................................................................................................. 5 1.4 QUANTITATIVE ANALYSIS OF THE EXTRACELLULAR SPACE ....... 7 2.0 INITIAL MOTIVATION ............................................................................................ 9 3.0 DETERMINATION OF ZETA POTENTIAL IN RAT ORGANOTYPIC HIPPOCAMPAL CULTURES.................................................................................................. 15 3.1 INTRODUCTION ............................................................................................. 16 3.1.1 Theory ............................................................................................................. 19 3.2 MATERIALS AND METHODS ...................................................................... 21 3.2.1 Chemicals and solutions ................................................................................ 21 3.2.2 Instrumentation ............................................................................................. 22 3.2.2.1 Capillary electrophoresis: .................................................................. 22 3.2.2.2 Apparatus for tissue experiments ...................................................... 23 3.2.2.3 Ag/AgCl electrodes .............................................................................. 23 vi 3.2.2.4 Injection capillary ............................................................................... 24 3.2.2.5 Imaging ................................................................................................ 24 3.2.3 Procedures ...................................................................................................... 25 3.2.3.1 Hippocampal organotypic slice cultures ........................................... 25 3.2.3.2 ζ-potential determination ................................................................... 26 3.2.3.3 Two-fluorophore experiments ........................................................... 26 3.3 RESULTS ........................................................................................................... 26 3.4 DISCUSSION ..................................................................................................... 31 3.4.1 Analysis of the method .................................................................................. 31 3.4.2 Analysis of the results .................................................................................... 33 3.4.3 Potential applications and implications ....................................................... 36 3.5 ACKNOWLEDGMENTS ................................................................................. 38 3.6 SUPPORTING MATERIAL ............................................................................ 38 3.6.1 Results ............................................................................................................. 38 3.6.2 Discussion ....................................................................................................... 39 3.6.2.1 Analysis of the method ........................................................................ 39 3.6.3 Materials and methods .................................................................................. 39 3.6.3.1 Chemicals and solutions ..................................................................... 39 3.6.3.2 Capillary electrophoresis .................................................................... 39 4.0 DETERMINATION OF ζ-POTENTIAL AND TORTUOSITY IN RAT ORGANOTYPIC HIPPOCAMPAL CULTURES FROM ELECTROOSMOTIC VELOCITY MEASUREMENTS UNDER FEEDBACK CONTROL .................................. 41 4.1 INTRODUCTION ............................................................................................. 42 vii 4.2 THEORY ............................................................................................................ 44 4.3 EXPERIMENTAL SECTION .......................................................................... 46 4.3.1 Chemicals and solutions ................................................................................ 46 4.3.2 Organotypic hippocampal slice cultures ..................................................... 47 4.3.3 Four-electrode potentiostat ........................................................................... 47 4.3.4 Apparatus for tissue experiments ................................................................ 49 4.3.5 Injection capillary .......................................................................................... 50 4.3.6 Imaging ........................................................................................................... 51 4.3.7 ζ-potential determination .............................................................................. 51 4.4 RESULTS ........................................................................................................... 53 4.5 DISCUSSION ..................................................................................................... 57 4.5.1 Comparison of methods ................................................................................ 57 4.5.2 Accuracy of the method ................................................................................ 60 4.6 SUPPORTING INFORMATION .................................................................... 63 5.0 IONTOPHORESIS INTO A POROUS MEDIUM DEPENDS ON THE ZETA POTENTIAL OF THE MEDIUM ............................................................................................ 65 5.1 INTRODUCTION ............................................................................................. 66 5.1.1 Theory ............................................................................................................
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